Integrity tests of HEPA filter are conducted regularly for the air conditioning systems of cleanrooms. For these test, DOP (dioctyl phthalate) is widely used as a tracer particle. But their influences on the human health and sometimes to products themselves are matters of concern. For that reason, we have developed a novel method in which aerosol particles of silica generated by spraying and drying a solution of silica in colloidal form are used as an alternative integrity test method of HEPA filters. This method is safer to human health and no influences to products even in electronic devices. HEPA filter that had artificial pinholes have been subjected to the integrity test and penetrated particle counts have been measured by both the DOP method and the newly developed silica particle counter method. The results obtained by both methods have been well coincided. It has been concluded that the newly developed silica aerosol method can be adopted as a better substitution for the widely used DOP test method.
Viral spiking studies were used to validate the capacity of our manufacturing process of a biological product derived from animal origin to inactivate or eliminate potential viral contaminants. Since the present study was intended for early Phase I & II clinical trials, two model viruses, Xenotropic Murine Leukemia Virus and polio virus, type 1, which represent a range of physical, chemical, and biological properties were selected for examination. It is generally recommended to take at least two different viral inactivation removed procedures for the robustness of the manufacturing process. We therefore selected a heat treatment and an ethanol purification step, two steps which held the potential for inactivation through independent mechanisms (i.e., physical and chemical inactivation, respectively). Finally, with the design of the experiment taken into consideration, the manufacturing steps were scaled-down and validated. Further, based upon the data collected during validation, the step parameters used for the present study were considered worst-cases. The result of the present spiking study for the two steps was a combined reduction of > 11 logs for polio virus and > 8 logs for X-MuLV which was the maximum attainable clearance given the spiking titer and dilution level for both viruses and both manufacturing steps.
100% inspection can not completely eliminate all of defect qualities from the lot, because of the limitation of detection rate. Three models of 100% inspection methods, which have different stopping rules, have been statistically compared by taking the detection rate into consideration. The three models of inspection methods are defined as follows. (A) Stop when we detect no defects for the first time. (B) Stop when we detect no defects for the second time. (C) Stop when we meet the first successive two no-detections of defects. It is found that, in view of the average number of total insepction times, the rule A is the best whereas in view of the average number of undetected defects the rule C is the best. The rule B stands between the rules A and C and is close to rule C. If we also consider the costs of inspection and undefected defects, the rule B is robust and when the probability to detect the defects is high then the rule A is excellent. The rule C is found to be too conservative.
Shizuoka Prefecture is the second largest prefecture of pharmaceutical production on the valve basis in Japan. Guidance Office of Pharmaceutical Affairs, Department of Health and Welfare has various functions such as inspection guidance and training program for industries. Concerning the GMP issues, there are two groups of field inspection consisting of 2 inspectors each in Shizuoka Prefectural Government. They spent 175 days in a year for field inspections as a rule. There are 59 pharmaceutical manufacturing facilities to which GMP is applied in Shizuoka Prefecture, among which 18 facilities are for manufacturing sterile products, 18 facilities are for manufacturing active pharmaceutical ingredients only, and other manufacturing facilities are for other dosage forms such as solid dosage form and external use. In the year of 1998, 266 cases were observed as objectionable, although some of which were minor ones or only recommendations. Among these 266 observations, 246 (92.5%) were concerning manufacturing control and management including the implementation of validation, and 19 were concerning equipments and construction features. These observations have been analyzed in details to show in what parts of GMP were week and should be improved hereafter. Followings are major parts which were observed as to be improved; (1) responsible persons should perform their job by themselves, (2) keen attention should be paid to the consistency among SOP, actual practice and manufacturing records, (3) change and/or omission of the written procedure should be performed only after official authorized approval, of the written procedure, (4) deficiencies were observed in lack of such records as cleaning, calibration, comparison between the standard yield and actual yield, trend analysis of % of rejected product by process inspection, and storage of raw data, (5) retest rule should be established in every case, (6) some deviations were observed in storage condition of products, raw materials and reference standards for laboratory test use, (7) complaint handling procedure and training procedure should be more clearly established to facilitate and secure the practice, (8) some inadequacies were observed in operation room condition, preparation vessel, and laboratory equipments.